Glucocerebrosidase mutations and Parkinson disease

Abstract

The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for the development of Parkinson disease (PD) resulted in a paradigm shift within the research landscape. Efforts to elucidate the mechanisms behind GBA1-associated PD have highlighted shared pathways in idiopathic PD including the loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction and altered autophagy-lysosomal pathway responsible for degradation of aggregated and misfolded a-synuclein. GBA1-associated PD exhibits subtle differences in phenotype and disease progression compared to idiopathic counterparts notably an earlier age of onset, faster motor decline and greater frequency of non-motor symptoms (which also constitute a significant aspect of the prodromal phase of the disease). GBA1-targeted therapies have been developed and are being investigated in clinical trials. The most notable are Ambroxol, a small molecule chaperone, and Venglustat, a blood-brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify the aetiology of GBA1-associated PD, enabling the development of a greater abundance of targeted therapies in this new era of precision medicine.

Keywords: Ambroxol; GBA1; Gaucher disease; Genetics; Neurodegeneration; Parkinson disease.

Fig. 1

The various approaches currently being explored in the search for neuroprotective therapies in GBA1-PD. Gene therapy may be used to replace the faulty GBA1 gene. Molecular chaperones may increase GCase activity by structurally correcting misfolded GCase. The use of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) to replenish GCase levels and reduce GlcCer accumulation in GBA1-PD, respectively, is being investigated